Cell-Free DNA-Based Blood Tests for Colorectal Cancer Screening: Current Advances, Challenges, and Future Perspectives

Background: Colorectal cancer (CRC) is a major cause of rising global rates of cancer-related morbidity and mortality. CRC rates are particularly increasing among younger populations; however, the implementation of effective CRC screening programs remains limited. Colonoscopy, the gold standard CRC screening technique, is restricted by complex procedures, invasive methods, and low patient adherence. Therefore, non-invasive screening through circulating cell-free DNA (cfDNA)-based blood tests is emerging as an effective alternative. Methods: This narrative review summarizes recent advances in cfDNA-based blood tests for colorectal cancer screening and early detection. Relevant English-language publications from 2021 to 2025 were searched on PubMed, ScienceDirect, and Google Scholar databases, supplemented by examination of reference lists. The study evaluated various diagnostic performance measures [sensitivity, specificity, and AUC (area under the curve)] and compared cfDNA-based approaches with previously established screening methods. Results: CRC detection and diagnostic efficacies of cfDNA-based technologies (mutation analysis, fragmentomics, integrated multi-omics approaches, and methylation profiling) have been reported in several recent studies. Fragmentomics and integrated multi-omics strategies have reported high diagnostic accuracy in a small number of heterogeneous, non-pooled studies. During a large-scale ECLIPSE study, involving an average-risk screening population, the Shield blood-based assay demonstrated 83.1% sensitivity for CRC, whereas the sensitivity for advanced precancerous lesions was only 13.2%. However, lack of assay standardization, low sensitivity for advanced precancerous lesions, methodological heterogeneity, and the need for prospective validation before routine clinical implementation remain major limitations. Conclusions: cfDNA-based non-invasive screening tools offer promising colorectal cancer detection accuracy. However, prospective validation, standardization, and optimization of analytical workflows are mandatory for the widespread clinical implementation of these techniques.